87 - Histone deacetylase inhibitors

Summary

Introduction

The base sequence of DNA provides the genetic code for proteins. The regulation of expression of genes is largely determined by the structure of the chromatin proteins associated with the DNA. Such epigenetic gene regulation refers to heritable and non-heritable gene expression that occurs without changes in DNA sequence (1–5). DNA is packaged in chromatin, which is structurally complex and dynamic, consisting of DNA, histones, and non-histone proteins (1,2). Nucleosomes are repeating units in chromatin composed of approximately 146 base pairs of two loops of DNA wrapped around an octamer core of pairs of histones H4, H3, H2A, and H2B. Histone amino tails are subject to post-translational modification by acetylation of lysines, methylation of lysines and arginines, phosphorylation of serines, ubiquitination of lysines, sumoylation, proline isomerization, and ADP-ribosylation (3–6). Among enzymes involved in chromatin protein structural modification are histone deacetylases (HDACs) and histone acetyltransferases (HATs), which determine the acetylation of histones and other proteins. Alterations of the structure and/or expression of HDACs and HATs occur in many cancers (7,8). In addition to histones, HDACs and HATs have many non-histone protein substrates that have a role in regulating gene expression, cell proliferation, cell migration, and cell death (8–13).

This chapter will focus on the biological activity of the zinc-dependent HDACs and the development of the HDAC inhibitors (HDACi) to treat cancers.